Novel raloxifene acid additon salts and/or solvates thereof, improved method for purification of said raloxifene acid addition salts and/or solvates thereof and pharmaceutical compositions comprising these

ABSTRACT

Raloxifene acid addition salts or solvates thereof, having improved dissolution properties in media comprising hydrochloric acid are described, compared with similar preparations based on raloxifene or raloxifene hydrochloride. The disclosed acid addition salts or solvates thereof show an improved bioavailability in media comprising hydrochloric acid, such as the gastric juice. The acid addition salts or solvates thereof are addition salts or solvates of raloxifene and a pharmaceutical acceptable acid selected among succinic acid, lactic acid, malonic acid or sulphuric acid. Further, crystalline forms of the raloxifene salts and solvates thereof are disclosed. The raloxifene acid addition salts and/or solvates thereof are useful for the preparation of pharmaceutical composition for oral administration capable of fast and reliable release of the active ingredients in the stomach of the patient, in particular for the treatment of cancer or osteoporosis, or for inhibiting cartilage degradation. A new method for preparation of raloxifene lactate is also disclosed.

The invention relates to acid addition salts and/or solvates of [6-hydroxy-2-(4-hydroxyphenyl)benzol[b]thien-3-yl][4-[2-(1-piperidinyl)-ethoxy]phenyl-, raloxifene, having high availability from media comprising dilute hydrochloric acid, such as gastric juice. In addition useful crystal forms of the acid addition salts and/or solvates are disclosed.

In another aspect the invention relates to pharmaceutical composition for oral administration comprising said novel acid addition salts and/or solvates thereof, preferably in crystalline form. The pharmaceutical compositions according to the invention are useful because the high availability from dilute hydrochloric acid, such as gastric juice, secures a high and reliable release of the active ingredient, raloxifene, in the stomach of the patient to whom said pharmaceutical composition have been administered.

Further the invention provides an improved method for preparation and purification of said acid addition salts and/or solvates thereof, which method provides for a quick and highly efficient purification of the crude raloxifene product.

BACKGROUND OF THE INVENTION

Raloxifene, [6-hydroxy-2-(4-hydroxyphenyl)benzol[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl-, is a well known compound having antiestrogene and antiandrogene activity. Raloxifene or raloxifene hydrochloride has proved useful for the preparation of pharmaceutical compositions for the treatment of cancer, osteoporosis and cartilage degradation.

Raloxifene, [6-hydroxy-2-(4-hydroxyphenyl)benzol[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl-, is also known as 6-hydroxy-2-(4-hydrophenyl)-3-[4-(2-piperidinoethoxy)-benzoyl]benzo-[b]-thiophene. Other names for raloxifene may also be found in the literature.

EP 62 503 A1 discloses benzothiophene compounds and process for preparing them. The disclosed compounds have antiestrogenic and antiandrogenic activity. Pharmaceutical preparation comprising said benzothiophene compounds are described, which preparations are useful for the treatment of cancers. A particular preferred compound is Raloxifene. Acid addition salts of the benzothiophene compounds with physiologically acceptable acids are also disclosed. As examples of physiologically acceptable acids are mentioned among others sulphuric acid, succinic acid and lactic acid.

In the manufacture of raloxifene the crude product in the reaction mixture was evaporated to dryness, redissolved and purified in several steps before the pure product was recovered as a crude product that was further purified to provide the desired compound.

The obtained free base was subsequent transformed into acid addition salts using usual techniques.

EP 584 952 discloses use of raloxifene or acid addition salts thereof for the treatment of osteoporosis. It is preferred to use an acid addition salt of raloxifene instead of raloxifene as a free base because the acid addition salts generally have improved dissolution properties compared to the free base. As examples of acids used for the acid addition salts are mentioned among others: hydrochloric acid, sulphuric acid, lactic acid, malonic acid and succinic acid. Raloxifene hydrochloride is the preferred acid addition salt.

EP 652 002 A1 discloses use or 2-phenyl-3-aroylbenzothiephenes or pharmaceutical acceptable acid addition salts thereof, such as raloxifene and raloxifene hydrochloride respectively, for the inhibition of cartilage degradation.

In WO 96/09045 raloxifene hydrochloride in crystalline form or as a solvate is described.

EP 910 369 discloses raloxifene hydrochloride in crystal form where the crystals are smaller than 50 microns, and EP 826 682 discloses raloxifene in an amorphous form having enhanced solubility.

At present most commercial available pharmaceutical compositions comprising raloxifene as active ingredient comprises raloxifene hydrochloride, because raloxifene hydrochloride is fairly soluble in aqueous solvents whereas raloxifene as free base is only sparingly soluble in aqueous solvents.

Despite the extensive experimentation of increasing the bioavailability of raloxifene there is still a need for providing the active compound in a form having increased availability of the active compound in order to provide pharmaceutical preparations for oral administration, which composition have a high availability of the active compound raloxifene from the upper gastrointestinal tract.

BRIEF DESCRIPTION OF THE INVENTION

The present invention relates to raloxifene acid addition salts and/or solvates having a high availability in dilute hydrochloric acid or gastric juice.

The present inventors have surprisingly discovered that the raloxifene acid addition salts and solvates according to the invention have high bioavailability of the active compound soon after ingestion. In particular the raloxifene salts and/or solvates according to the invention have improved intrinsic dissolution properties in the presence of hydrochloric acid such as in gastric juice, compared with the commonly used raloxifene acid addition salt, raloxifene hydrochloride.

In a further aspect the invention relates to new and particular useful crystal forms of said novel raloxifene acid addition salts or solvates thereof.

In an even further aspect the invention relates to pharmaceutical compositions comprising said novel raloxifene acid addition salts and solvates thereof, which compositions after the ingestion thereof is capable of releasing the active compound raloxifene in higher amounts, compared with the frequently used compound raloxifene hydrochloride.

A further aspect of the invention relates to a new and improved method for preparation of raloxifene lactate.

SHORT DESCRIPTION OF THE FIGURES

FIG. 1 shows a differential scanning calorimetric chart (DSC) for raloxifene DL-lactate hemihydrate. The chart was recorded at a rate of 20° C./min.

FIG. 2 shows the X-ray diffraction pattern for crystalline raloxifene DL-lactate hemihydrate.

FIG. 3 shows a DSC for raloxifene L-lactate hemihydrate. The chart was recorded at a rate of 20° C./min.

FIG. 4 shows the X-ray diffraction pattern for crystalline ralbxifene L-lactate hemihydrate.

FIG. 5 shows a DSC for raloxifene L-lactate ¼-hydrate. The chart was recorded at a rate of 20° C./min.

FIG. 6 shows the X-ray diffraction pattern for crystalline raloxifene L-lactate ¼-hydrate.

FIG. 7 shows the Intrinsic Dissolution Rate for raloxifene succinate compared with raloxifene hydrochloride.

FIG. 8 shows the Intrinsic Dissolution Rate for raloxifene DL-lactate hemihydrate compared with raloxifene hydrochloride.

FIG. 9 shows the Intrinsic Dissolution Rate for raloxifene L-lactate ¼-hydrate compared with raloxifene hydrochloride.

FIG. 10 shows the Intrinsic Dissolution Rate for raloxifene L-lactate hemihydrate compared with raloxifene hydrochloride.

FIG. 11 shows the Intrinsic Dissolution Rate for raloxifene malonate compared with raloxifene hydrochloride.

FIG. 12 shows the Intrinsic Dissolution Rate for raloxifene sulphate compared with raloxifene hydrochloride.

DETAILED DESCRIPTION OF THE INVENTION

The inventors have realized that even though raloxifene hydrochloride is fairly soluble in aqueous media the solubility appear to decreases significant in aqueous media comprising hydrochloric acid.

By the term “dilute hydrochloric acid” or “media comprising hydrochloric acid” as used herein is meant an acidic aqueous solution containing chloride ions. Gastric juice is a preferred example of dilute hydrochloric acid.

The skilled person will appreciate that gastric juice contains hydrochloric acid. Further the skilled person will appreciate that the composition of gastric juice apart from individual variations depends on various factors such as time of day, time since last meal and size and composition of said last meal. However for the purpose of the present description, the gastric juice can be regarded as a dilute solution of hydrochloric acid usually having a pH value in the range of approximately 1-3, possible also containing sodium chloride in an amount of 1-3% w/w. In the duodenum and the upper part of the small intestines the pH raises up to approximately 4-6 or even higher.

The raloxifene acid addition salts and/or solvates thereof according to the invention have dissolution properties in dilute hydrochloric that secure a high bioavailability of these compounds. In particular the compounds according to the invention have higher intrinsic dissolution rates in dilute hydrochloric acid compared with free raloxifene or raloxifene hydrochloride.

The terms “high availability”, “high bioavailability” or grammatical equivalent expressions are according to the invention intended to mean that the raloxifene salts and/or solvates thereof are available for assimilation from the gastro intestinal tract to the circulation of the body in high amount soon after ingestion. In particular the raloxifene salts and/or solvates thereof have higher bioavailability compared with the presently frequently used raloxifene compounds, i.e. raloxifene as free base or raloxifene hydrochloride.

In accordance with the present invention the term “upper gastrointestinal tract” is intended to mean the oesophagus, the stomach, the duodenum and the upper part of the small intestines. It is believed that the assimilation of raloxifene mainly takes place in the upper gastrointestinal tract.

The inventors have surprisingly discovered that acid addition salts and/or solvates thereof according to the invention appear to have a higher bioavailability from acidic solutions comprising sodium chloride compared to raloxifene as free base or raloxifene hydrochloride in crystalline or amorphous form. Consequently, pharmaceutical preparations for oral administration comprising acid addition salts and /or solvates thereof according to the invention will provide the active compound raloxifene faster and/or in an higher amount compared with pharmaceutical preparations comprising raloxifene hydrochloride or raloxifene as free base.

Thus in one aspect the invention provides pharmaceutical preparations for oral administration comprising a raloxifene acid addition salt and/or solvate thereof according to the invention as the active ingredient. These preparations provide the active compound raloxifene in a form having high bioavailability when said preparations are ingested and dispersed in gastric juice.

The high availability of the active compound secures that a therapeutic regimen using the pharmaceutical preparations according to the invention may be performed with higher accuracy because the attending physician will know that the complete dose or at least a major part thereof will be available for assimilation from the gastro intestinal tract soon after the ingestion the pharmaceutical preparations according to the invention.

Therefore pharmaceutical compositions comprising such compounds may provide for a higher efficiency of the of said compounds by the individuals to whom said compositions are administered, compared with corresponding pharmaceutical compositions based on raloxifene or raloxifene hydrochloride.

Thus the pharmaceutical preparations according to the invention provide a fast and high availability of the active compound in the stomach soon after intake of the preparation.

Alternatively or additionally, the high availability of the active compounds according to the invention may render the need for micronization superfluous, which micronization in the prior art have been used to increase the bioavailability of raloxifene compounds, cf. EP 910 369.

Therefore in one aspect the present invention relates to pharmaceutical compositions for oral administration comprising raloxifene acid addition salts and/or solvates thereof, having fast and high bioavailability of the active compound raloxifene.

According to the invention the acid addition salts and/or solvates of raloxifene is selected among the succinate, lactate, malonate or the sulphate.

The lactate may be in the D or L form or a mixture thereof such as racemic mixtures. Further the lactate may be isolated as a solvate.

Because succinic acid, malonic acid and sulphuric acid have two acid groups per molecule, compounds of these acids and raloxifene may be isolated as either mono or di acid addition salts and/or solvates thereof having either one or two raloxifene molecules per acid molecule respectively.

In a preferred embodiment the acid addition salt and/or solvates thereof according to the invention is raloxifene DL-lactate, and in a particular preferred embodiment the acid addition salt is raloxifene L-lactate.

The skilled person will appreciate that the acid addition salts according to the invention may be isolated as solvates, which in the present description is to be understood as compounds where solvate molecules are included in the solid compounds, usually in defined stoichiometric amounts.

For some compounds more that one solvate may be isolated, which solvates differ only with respect of the solvent incorporated in the solid and the number of solvate molecules per molecule of the acid addition salt.

Preferred solvates according to the invention are solvates with pharmaceutically acceptable solvents such as water or alcohols having less than 5 carbon atoms, even more preferred selected among water, methanol, ethanol, propanol and 2-propanol.

Examples of solvates according to the invention include raloxifene L-lactate hemihydrate, raloxifene D-lactate hemihydrate, raloxifene DL-lactate hemihydrate, raloxifene L-lactate ¼-hydrate, raloxifene D-lactate ¼-hydrate, raloxifene DL-lactate ¼-hydrate and raloxifene sulphate (2-propanol solvate).

Preferred compounds according to the invention include raloxifene D-lactate hemihydrate, raloxifene DL-lactate hemihydrate, raloxifene L-lactate hemihydrate and raloxifene L-lactate ¼-hydrate, where raloxifene L-lactate hemihydrate and raloxifene L-lactate ¼-hydrate is particular preferred.

It is well known that organic compounds may be isolated in crystalline form or in amorphous form. Generally it is preferred to provide compounds in crystalline form because crystallisation usually is accompanied by a purification of the compound, and further, because crystals are more well defined solids than amorphous materials the properties of compounds in-crystalline form varies less than materials in amorphous form.

Therefore the raloxifene acid addition salts and/or solvates according to the invention in crystalline form provides another aspect of the invention.

The raloxifene acid addition salts in crystalline form according to the invention are raloxifene lactate, raloxifene malonate and raloxifene succinate, which all exist as distinct crystalline compounds, and raloxifene sulphate, which may be isolated in crystalline form as a 2-propanol solvate having one molecule of 2-propanol incorporated per two raloxifene molecules.

For some of the raloxifene acid addition salts and/or solvates thereof according to the invention more that one crystal form may be possible, where the different crystal forms may be prepared dependent on the solvent, temperature etc, as it will be known within the area.

Pharmaceutical preparations for oral administration comprising raloxifene salts and/or solvates thereof according to the invention may be prepared using pharmaceutical techniques well known within the area e.g. from text books such as Remington's manual.

For example may the raloxifene compounds according to the invention be formed for oral administration into tablets, capsules etc. In forming the pharmaceutical preparations the compounds according to the invention may be mixed with usual fillers and excipiens, such as disintegration agents, lubricants, swelling agents. The preparations may also be coated according to well-known techniques.

Raloxifene acid addition salts and/or solvates may be prepared using methods known for the skilled person.

For example may any acid addition salt be converted into the free base and subsequently the free base may be converted into another acid addition salt by known procedures.

Usually raloxifene is prepared directly as raloxifene hydrochloride.

The present inventors have observed that in contrast to raloxifene and previously tested acid addition salts thereof e.g. raloxifene hydrochloride, raloxifene lactate can easily be crystallized in high yield and high purity from an alcoholic solution.

It has been realized that this property may be used for a quick and high efficient purification of raloxifene lactate from an intermediate in the synthesis of raloxifene.

Thus raloxifene lactate may be prepared directly without previous isolation of free raloxifene or raloxifene hydrochloride using the following procedure:

To a solution of the compound having the general formula I

wherein R represents two independently selected hydroxyl protection groups,

in a solvent a suitable reagent is added in order to remove the protection groups. Next the pH of the mixture is adjusted to neutral reaction using lactic acid, and thereafter raloxifene lactate may be precipitated and isolated.

This procedure according to the invention is beneficial because raloxifene lactate is easily crystallized from such a mixture, particular if the solvent is an alcohol having 1-5 carbon atoms. The easy crystallisation of raloxifene lactate represents a high and easy purification of the raloxifene from the reaction mixture. The crystallized raloxifene lactate may be further purified by recrystallization from an alcohol.

The compound having the formula I is known within the art from e.g EP 875 511 A1, where it is called formula VII, and from EP 62 503, where it is prepared by the reaction scheme (B).

The group R may be any hydroxyl protection group known to the skilled person. For example, R may be selected from C₁-C₄ alkyl, C₅-C₇ cycloalkyl, benzyl —COR² or SO₂R², wherein R² is C₁-C₄ primary or secondary alkyl, C₁-C₃ fluoroalkyl, C₁-C₃ chloroalkyl, C₁-C₄ alkylphenyl, C₁-C₄ alkoxyphenyl, mono- or dinitrophenyl or mono- or di(chloro or fluoro)phenyl.

The two R groups may be the same or different. It is preferred that the two R groups are selected so that the similar conditions are needed to remove the two groups.

The term “neutral reaction” is intended to mean that the mixture has a pH value in the range of 6-8, preferably 7.0-7.5.

The chemical used to remove the protection groups may be any chemical known to be able to remove the particular used protection groups. It is within the skills of the practitioner to select a suitable chemical to remove the protection group for each selected protection group.

The solvent used for the reaction may in principle be any solvent that is capable of dissolving the reagents and does not participate in reactions with any of the ingredients of the reaction mixture under the conditions applied. Preferred solvents are alcohols having 1 to 5 carbon atoms. Particular preferred solvents are monovalent alcohols having 1 to 5 carbon atoms, where methanol, ethanol, propanol and 2-propanol are the most preferred solvents.

The obtained raloxifene lactate may be recrystallized in order to obtain the compound in even higher purity.

As solvent for the crystallization may in principle be used any alcohol having suitable melting and boiling temperatures. Alcohols having 1 to 5 carbon atoms and one hydroxyl group are preferred.

As examples of preferred alcohols can be mentioned methanol, ethanol, propanol, 2-propanol, butanol, 2-butanol, neobutyl alcohol, pentanol, 2-pentanol and 3-pentanol.

It is within the abilities of the skilled practitioner to select a suitable solvent for crystallization of particular selected compound of the invention.

Ethanol is a particular preferred alcohol.

The concentration of alcohol in the crystallization mixture should be higher that 90%, preferably higher that 95%. A particular preferred solvent for the crystallisation reaction is 96% ethanol.

The crystallisation may be performed using procedures known within the area. Further as it will be known for the skilled person it may be advantageous to add seeding crystals to the crystallization mixture to promote crystallisation.

Thus in another aspect the invention relates to a method for purification of raloxifene lactate from an alcoholic solution of raloxifene comprising addition of lactate, adjusting pH and temperature of the obtained mixture and isolation of the formed crystalline raloxifene lactate.

In a preferred embodiment the alcoholic solution of raloxifene is the reaction mixture of the synthesis of raloxifene if necessary after a change of solvent.

The invention is further illustrated by way of examples, which are solely provided for illustration and should not be considered at limiting in any way.

EXAMPLES Example 1 [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl-, succinate; Raloxifene succinate

37.9 g (˜0.6 mol) pulverized potassium hydroxide (>85%) is dissolved in 1250 ml 2-propanol, with stirring and addition of nitrogen, over approximately 30 minutes. 100 g (0.196 mol) raloxifene hydrochloride is added in small portions in such a way that temperature is kept below 36° C. After addition of raloxifene hydrochloride, the deep red suspension is stirred for 30-45 minutes until a deep red solution appears. Reminiscence of insoluble product may be filtered off. 1 L of a solution of 70.85 g (0.6 mol) succinic acid in 2-propanol/water (80:20) is added with violent stirring during 1-1.5 hours. The mixture is now stirred further at room temperature for 18 hours, and the precipitate is filtered off as white/yellowish crystals. The product is now washed 2 times with 40 ml 2-propanol and then dried in vacuo at 55-65° C. for 16 hours to give 178.5 g crude product.

The crude product is stirred with 890 ml of water for 3 hours and then filtered off and washed 3 times with 100 ml of water. The product is dried in vacuo at 55-65° C. for 16 hours to give 89.7 g (77.3% yield) of product.

Mp: dec. >195° C., mp. ˜225° C.

Elemental analysis C₃₃H₃₃NO₈S:

Calculated: C, 64.96%; H, 5.62%; N, 2.37%; S. 5.42%

Found: C, 65.64%; H, 5.49%; N, 2.60%; S, 5.99%

IR:

3406 cm⁻¹, 3145 cm⁻¹, 2945 cm⁻¹, 2691 cm⁻, 1642 cm⁻, 1597 cm⁻¹, 1541 cm⁻¹, 1501 cm⁻¹, 1457 cm⁻¹, 1430 cm⁻¹, 1421 cm⁻¹, 1356 cm⁻¹, 1259 cm⁻¹, 1234 cm⁻¹, 1171 cm⁻¹, 1125 cm⁻, 1108 cm⁻¹, 1079 cm⁻¹, 1047 cm⁻¹, 1038 cm⁻¹, 907 cm⁻¹, 839 cm⁻¹, 807 cm⁻¹, 623 cm⁻¹

XRD: D 2Theta I(rel) I(abs)) FWHM 13.195230 6.6933 20.78 8475 0.1400 9.695642 9.1137 13.43 5476 0.0300 9.304945 9.4972 18.19 7419 0.1300 8.394523 10.5300 13.26 5407 0.1000 7.944460 11.1283 14.15 5768 0.1000 7.708667 11.4699 17.61 7180 0.1200 7.526675 11.7482 12.32 5023 0.0898 7.323294 12.0756 15.22 6205 0.1000 7.160495 12.3512 13.04 5316 0.0800 6.926815 12.7696 23.68 9655 0.1300 6.606409 13.3917 29.08 11856 0.1400 6.463392 13.3894 14.45 5891 0.0898 6.285432 14.0789 21.24 8662 0.1200 6.127742 14.4432 63.63 25947 0.1200 5.961999 14.8469 15.55 6342 0.0900 5.875574 15.0665 15.77 6430 0.0898 5.788967 15.2933 16.15 6585 0.1400 5.624221 15.7441 34.74 14167 0.1200 5.453763 16.2394 22.89 9334 0.1300 5.276560 16.7887 12.71 5182 0.1200 5.095057 17.3913 14.19 5786 0.1100 5.020392 17.6520 11.12 4535 0.0898 4.835944 18.3309 18.30 7461 0.1200 4.765096 18.6059 18.62 7591 0.1100 4.630456 19.1519 65.88 26864 0.1600 4.525518 19.6003 15.16 6180 0.0800 4.484997 19.7792 24.48 9982 0.1000 4.376528 20.2745 18.78 7659 0.1000 4.352225 20.3889 19.11 7790 0.1000 4.227757 20.9959 29.39 11984 0.1000 4.191265 21.1808 56.82 23171 0.0800 4.158052 21.3520 40.16 16377 0.0898 4.101947 21.6475 17.14 6988 0.0800 4.062068 21.8626 19.79 8072 0.1000 4.010082 22.1496 11.70 4771 0.0600 3.921660 22.6556 100.00 40776 0.1300 3.860487 23.0194 29.04 11842 0.1100 3.813566 23.3066 19.25 7850 0.1100 3.732687 23.8189 19.33 7884 0.1300 3.694791 24.0669 22.47 9161 0.1100 3.644300 24.4054 18.84 7680 0.1400 3.544078 25.1067 13.63 5556 0.0700 3.496160 25.4565 16.28 6637 0.0898 3.446458 25.8299 20.36 8300 0.2100 3.398344 26.2021 12.35 5036 0.1200 3.373032 26.4022 8.82 3597 0.0898 3.305938 26.9481 14.08 5741 0.1100 3.281940 27.1489 10.08 4112 0.0898 3.260437 27.3314 9.66 3937 0.0898 3.227083 27.6194 19.22 7838 0.1200 3.179256 28.0434 16.28 6640 0.2600 3.146269 28.3435 8.89 3627 0.0898 3.121159 28.5764 9.58 3907 0.0900 3.097691 28.7975 10.64 4337 0.0400 3.074307 29.0213 19.64 8008 0.1200 3.032262 29.4328 10.17 4148 0.1300 3.010128 29.6541 9.43 3847 0.0898

Example 2 16-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl-, malonate; Raloxifene malonate

37.9 g (˜0.6 mol) pulverized potassium hydroxide (>85%) is dissolved in 1250 ml 2-propanol, with stirring and addition of nitrogen, over approximately 30 minutes. 100 g (0.196 mol) raloxifene hydrochloride is added in small portions in such a way that temperature is kept below 30° C. After addition of raloxifene hydrochloride, the deep red suspension is stirred for 30-45 minutes until a deep red solution appears. Reminiscence of insoluble product may be filtered off. 260 ml of a solution of 62.76 g (0.6 mol) malonic acid in 2-propanol/water is added with violent stirring during 1-1.5 hours. The mixture is now stirred further at room temperature for 18 hours, and the precipitate is filtered off as white/yellowish crystals. The product is now washed 2 times with 40 ml 2-propanol and then dried in vacuo at 55-65° C. for 16 hours to give 182.4 g crude product.

The crude product is stirred with 912 ml of water for 3 hours and then filtered off and dried in vacuo at 55-65° C. for 16 hours to give 98.7 g (87.2% yield) of crude product. The crude product is boiled for 5 minutes in 500 ml 2-propanol and then cooled at 10° C. for 30 minutes. The product is filtered off and washed with 100 ml 2-propanol and then dried in vacuo to give 90.8 g (97%) of the product.

Mp:. 226-227° C.

Elemental analysis C₃₂H₃₁NO₈S:

Calculated: C, 64.46%; H, 5.41%; N, 2.42%; S, 5.55%

Found: C, 64.86%; H, 5.55%; N, 2.57%; S, 5.87%

IR:

3388 cm⁻¹, 3199 cm⁻¹, 2950 cm⁻¹, 2683 cm⁻¹, 2543 cm⁻¹, 1643 cm⁻¹, 1597 cm⁻¹, 1539 cm⁻¹, 1502 cm⁻¹, 1467 cm⁻¹, 1421 cm⁻¹, 1355 cm⁻¹, 1306 cm⁻¹, 1255 cm⁻¹, 1169 cm⁻¹, 1038 cm⁻¹, 952 cm⁻¹, 907 cm⁻¹, 839 cm⁻¹, 808 cm⁻¹, 645 cm⁻¹, cm⁻¹, 623 cm⁻¹

XRD: D 2Theta I(rel) I(abs) FWHM 14.385166 6.1391 36.51 6471 0.0100 13.125024 6.7292 38.91 6896 0.1300 10.305386 8.5734 37.32 6614 0.1700 9.279238 9.5236 39.85 7062 0.1300 8.860721 9.9745 34.60 6133 0.0900 8.510328 10.3863 33.27 5895 0.0900 8.314361 10.6318 33.02 5852 0.0800 7.947949 11.1234 41.61 7375 0.1600 7.265135 12.1727 35.79 6343 0.1300 6.882996 12.8512 29.65 5254 0.0300 6.537915 13.5326 60.19 10667 0.1800 6.258251 14.1404 61.12 10833 0.2100 6.003203 14.7444 31.92 5657 0.1200 5.877911 15.0605 29.17 5170 0.0600 5.794580 15.2784 29.33 5198 0.0200 5.663226 15.6349 49.63 8796 0.1300 5.550457 15.9547 36.61 6487 0.0800 5.354103 16.5438 55.84 9897 0.2200 5.134028 17.2583 30.18 5349 0.1378 5.023848 17.6397 55.21 9784 0.2100 4.836637 18.3283 36.13 6404 0.1400 4.700761 18.8628 71.64 12696 0.1600 4.644808 19.0922 86.46 15323 0.1500 4.538522 19.5436 61.36 10874 0.1300 4.472256 19.8361 50.40 8931 0.1000 4.347111 20.4132 37.86 6709 0.1000 4.247918 20.8951 88.12 15616 0.2300 4.161428 21.3344 73.93 13101 0.1600 4.085803 21.7341 37.19 6591 0.1100 4.019584 22.0966 35.60 6309 0.1500 3.921695 22.6554 100.00 17722 0.1700 3.765729 23.6059 50.70 8986 0.2000 3.703455 24.0097 34.79 6166 0.1200 3.638542 24.4446 47.30 8382 0.1900 3.499221 25.4339 44.29 7849 0.2000 3.426872 25.9801 43.63 7732 0.2200 3.292398 27.0610 23.39 4145 0.1000 3.253755 27.3886 25.03 4435 0.1400 3.192249 27.9269 22.18 3931 0.1400 3.094846 28.8246 28.68 5083 0.3000 3.034329 29.4123 27.30 4338 0.1900

Example 3 [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl- sulphate (2-propanol solvat); Raloxifene sulphate (2-propanol solvate)

3.79 g (˜0.06 mol) pulverized potassium hydroxide (>85%) is dissolved in 125 ml 2-propanol, with stirring and addition of nitrogen, over approximately 30 minutes. 10 g (0.0196 mol) raloxifene hydrochloride is added in small portions in such a way that temperature is kept below 30° C. After addition of raloxifene hydrochloride, the deep red suspension is stirred for 30-45 minutes until a deep red solution appears. Reminiscence of insoluble product may be filtered off. A solution of 6.5 g 96% (0.6 mol) sulphuric acid in 15 ml 2-propanol and 12 ml of water is added with violent stirring during 1-1.5 hours (weakly exothermic). The mixture is now stirred further at room temperature for 18 hours, and the precipitate is filtered off as white crystals. The product is now washed 2 times with 4 ml 2-propanol and then dried in vacuo at 55-65° C. for 16 hours to give 15 g crude product.

The crude product is stirred with 76 ml of water for 3 hours and then filtered off and washed 3 times with 100 ml of water. The product is dried in vacuo at 55-65° C. for 16 hours to give 8.6 g (% yield) of product. The product is boiled with 38 ml of 2-propanol for 5 minutes and then cooled on to 0-5° C. for 30 minutes and filtered. The product is washed with 2 times with 5 ml 2-propanol, and dried in vacuum at 70-75° C.

Mp:. 262-263° C.

Elemental analysis C₅₉H₆₄N₂O₁₃S₃:

Calculated: C, 64.46%; H, 5.41%; N, 2.42%; S, 5.55%

Found: C, 64.86%; H, 5.55%; N, 2.57%; S, 5.87%

IR:

3199 cm⁻¹, 2963 cm⁻¹, 2723 cm⁻¹, 2693 cm⁻¹, 2659 cm⁻¹, 2559 cm⁻¹, 1653 cm⁻¹, 1597 cm⁻¹, 1547 cm⁻¹, 1501 cm⁻¹, 1467 cm⁻¹, 1437 cm⁻¹, 1419 cm⁻¹, 1344 cm⁻¹, 1308 cm⁻¹, 1268 cm⁻¹, 1251 cm⁻¹, 1233 cm⁻¹, 1167cm⁻¹, 1037 cm⁻¹, 1020 cm⁻¹, 952 cm⁻¹, 907 cm⁻¹, 839 cm⁻¹, 823 cm⁻¹, 809 cm⁻¹, 627 cm⁻¹, 524 cm⁻¹.

XRD: D 2Theta I(rel) I(abs) FWHM 14.374007 6.1439 26.57 5009 0.0900 10.303750 8.5748 29.62 5583 0.1300 9.201529 9.6042 26.22 4942 0.1100 8.871726 9.9621 29.84 5624 0.1300 8.569965 10.3138 22.25 4195 0.0400 8.320378 10.6241 25.97 4896 0.1200 7.945119 11.1274 38.65 7286 0.1300 7.514174 11.7678 20.56 3876 0.1041 7.205108 12.2745 25.04 4721 0.1400 6.537437 13.5336 66.78 12590 0.1400 6.228787 14.2076 21.88 4126 0.1100 5.628329 15.7325 20.71 3904 0.0900 5.540447 15.9837 27.40 5166 0.1100 5.322476 16.5489 64.98 12249 0.1500 5.138694 17.2425 21.65 4082 0.1100 5.020317 17.6522 64.05 12074 0.1400 4.706881 18.8381 100.00 18851 0.1300 4.618097 19.2036 60.47 11400 0.0800 4.538129 19.5453 59.35 11189 0.1100 4.471816 19.8381 67.03 12636 0.1200 4.261964 20.8255 54.78 10327 0.1100 4.204757 21.1121 51.35 9680 0.1600 4.156029 21.3625 46.65 8794 0.1041 4.093305 21.6938 25.93 4888 0.0900 4.035960 22.0058 24.21 4563 0.1800 3.937182 22.5651 25.37 4784 0.1200 3.835400 23.1721 22.17 4179 0.0900 3.796528 23.4127 40.94 7718 0.0900 3.767170 23.5978 61.03 11505 0.1100 3.691303 24.0899 20.10 3790 0.1500 3.639317 24.4393 47.20 8897 0.1200 3.590489 24.7769 28.23 5321 0.1600 3.511060 25.3467 29.66 5592 0.1100 3.478586 25.5873 23.70 4468 0.1041 3.416539 26.0601 37.38 7047 0.1900 3.355389 26.5436 20.28 3823 0.1300 3.314637 26.8760 17.08 3220 0.1200 3.271015 27.2413 15.24 2874 0.0600 3.252583 27.3987 14.71 2773 0.1041 3.100446 28.7714 23.04 4344 0.1200 3.079703 28.9694 19.73 3720 0.1041 3.033828 29.4172 29.23 5511 0.1300 3.009744 29.6580 15.28 2880 0.1041 2.937725 30.4024 13.30 2507 0.1700

Example 4 [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl-, DL-lactate hemihydrate; Raloxifene DL-lactate hemihydrate

37.9 g (˜0.6 mol) pulverized potassium hydroxide (>85%) is dissolved in 1250 ml 2-propanol, with stirring and addition of nitrogen, over approximately 30 minutes. 100 g (0.196 mol) raloxifene hydrochloride is added in small portions in 30 such a way that temperature is kept below 30° C. After addition of raloxifene hydrochloride, the deep red suspension is stirred for 30-45 minutes until a deep red solution appears. Reminiscence of insoluble product may be filtered off. A solution of 67.6 g 85% DL-lactic acid (0.6 mol) in 200 ml of 2-propanol is added with violent stirring during 1-1.5 hours. The mixture is now stirred further at room temperature for 18 hours, and the precipitate is filtered off as white/yellowish crystals. The product is now washed 2 times with 40 ml 2-propanol and then dried in vacuo at 55-65° C. for 16 hours to give 109 g crude product.

The crude product is stirred with 545 ml of water for 3 hours and then filtered off and washed 2 times with 75 ml of water. The product is dried in vacuo at 75-80° C. for 16 hours to give 92.7 g (83.9% yield) of product.

Mp: 196-198° C.

Elemental analysis C₃₄H₃₃NO₇S (½H₂O):

Calculated: C, 65.00%; H, 5.98%; N, 2.45%; S, 5.60%

Found: C, 65.07%; H, 5.93%; N, 2.37%; S, 5.34%

IR:

3385 cm⁻¹, 3223 cm⁻¹, 2940 cm⁻¹, 2675 cm⁻¹, 1641 cm⁻¹, 1598 cm⁻¹, 1542 cm⁻¹, 1502 cm⁻¹, 1467 cm⁻¹, 1421 cm⁻¹, 1349 cm⁻¹, 1307 cm⁻¹, 1253 cm⁻¹, 1171 cm⁻¹, 1123 cm⁻¹, 1038 cm⁻¹, 953 cm⁻¹, 908 cm⁻¹, 837 cm⁻¹, 808 cm⁻¹, 649 cm⁻¹, 623 cm⁻¹, cm⁻¹, 532 cm⁻¹, 514 cm⁻¹.

The product was further analysed using differential scanning calorimetry using a METTLER TOLEDO STAR® system, according to the instructions of the manufacturer. The differential scanning calorimetric chart (DSC) is shown in FIG. 1.

Further the product was analysed by X-ray diffraction analysis using the STOE Powder diffraction system. The result is shown in FIG. 2, and is also listed numerically below.

XRD: D 2Theta I(rel) I(abs) FWHM 13.595814 6.4959 28.40 12683 0.1400 10.855533 8.1382 16.15 7211 0.1200 9.849394 8.9711 32.17 14369 0.1000 9.534325 9.2682 66.95 29898 0.1300 8.150249 10.8465 45.20 20188 0.1300 7.240730 12.2138 63.53 28374 0.1400 6.769843 13.0670 18.42 8227 0.1500 6.272666 14.1077 75.67 33794 0.1900 5.818832 15.2143 13.28 5933 0.2000 5.657337 15.6513 18.07 8070 0.1300 5.505030 16.0872 10.51 4692 0.1000 5.261933 16.8357 17.48 7806 0.1400 5.089504 17.4104 16.14 7210 0.1000 5.001569 17.7189 41.94 18732 0.0900 4.958950 17.8725 29.16 13023 0.1148 4.797388 18.4795 19.39 8660 0.1100 4.669322 18.9910 49.20 21972 0.1400 4.574684 19.3876 63.21 28227 0.1000 4.533019 19.5676 44.94 20071 0.1148 4.440548 19.9792 32.70 14604 0.1200 4.301886 20.6301 100.00 44659 0.1500 4.155406 21.3657 78.00 34833 0.1600 4.059049 21.8797 27.53 12296 0.1800 3.960846 22.4285 25.59 11427 0.1000 3.907408 22.7393 83.48 37282 0.1200 3.865461 22.9894 16.46 7350 0.1148 3.828892 23.2120 17.46 7798 0.0900 3.773130 23.5599 50.71 22649 0.1200 3.716486 23.9243 23.06 10300 0.1300 3.652238 24.3515 15.79 7053 0.1800 3.584725 24.8174 12.91 5764 0.1500 3.486791 25.5261 30.45 13600 0.1200 3.439149 25.8858 22.21 9919 0.1300 3.396267 26.2184 17.86 7978 0.1100 3.370045 26.4261 12.48 5572 0.1148 3.329320 26.7553 9.21 4113 0.1100 3.292728 27.0582 11.81 5274 0.1000 3.278070 27.1815 11.25 5026 0.1148 3.218620 27.6935 21.24 9485 0.1900 3.167986 28.1452 13.80 6162 0.0900 3.143230 28.3715 30.33 13546 0.1000 3.095423 28.9191 14.02 6260 0.1200 3.024921 29.5058 11.56 5161 0.1400 3.007253 29.6831 13.40 5984 0.1300

Example 5 [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl-, L-lactate hemihydrate; Raloxifene L-lactate hemihydrate

37.9 g (˜0.6 mol) pulverized potassium hydroxide (>85%) is dissolved in 1250 ml 2-propanol, with stirring and addition of nitrogen, over approximately 30 minutes. 100 g (0.196 mol) raloxifene hydrochloride is added in small portions in such a way that temperature is kept below 30° C. After addition of raloxifene hydrochloride, the deep red suspension is stirred for 30-45 minutes until a deep red solution appears. Reminiscence of insoluble product may be filtered off.

A solution of 67.6 g 85% L-lactic acid (0.6 mol) is added with violent stirring during 1-1.5 hours. The mixture is now stirred further at room temperature for 18 hours, and the precipitate is filtered off as white/yellowish crystals. The product is now washed 2 times with 40 ml 2-propanol and then dried in vacuo at 55-65° C. for 16 hours to give 109 g crude product.

The crude product is stirred with 545 ml of water for 3 hours and then filtered off and washed 2 times with 75 ml of water. The product is dried in vacuo at 75-80° C. for 16 hours to give 92.7 g (83.9% yield) of product.

Mp:. 134-136° C.

Elemental analysis C₃₁H₃₃NO₇S (½H₂O):

Calculated: C, 65.00%; H, 5.98%; N, 2.45%; S, 5.60%

Found: C, 65.08%; H, 6.14%; N, 2.58%; S, 5.78%

IR:

3167 cm⁻¹, 2934 cm⁻¹, 1641 cm⁻¹, 1627 cm⁻¹, 1593 cm⁻¹, 1543 cm⁻¹, 1500 cm⁻¹, 1469 cm⁻¹, 1433 cm⁻¹, 1350 cm⁻¹, 1314 cm⁻¹, 1259 cm⁻¹, 1170 cm⁻¹, 1128 cm⁻¹, 1103 cm⁻¹, 1033 cm⁻¹, 908 cm⁻¹, 836 cm⁻¹, 809 cm⁻¹.

The product was analysed using differential scanning calorimetry using a METTLER TOLEDO STAR® system, according to the instructions of the manufacturer. The differential scanning calorimetric chart (DSC) is shown in FIG. 3.

Further the product was analysed by X-ray diffraction analysis using the STOE Powder diffraction system. The result is shown in FIG. 4, and is also listed numerically below.

XRD: D 2Theta I(rel) I(abs) FWHM 14.639874 6.0322 17.56 6122 0.1200 13.207421 6.6871 15.07 5254 0.1200 10.875932 8.1229 80.41 28029 0.1200 9.268456 9.5347 22.67 7903 0.1200 8.140638 10.8593 17.92 6247 0.1200 7.488503 11.8083 15.59 5433 0.1000 7.310331 12.0971 12.47 4347 0.0800 7.089508 12.4754 25.79 8991 0.1000 6.931874 12.7603 12.78 4454 0.0900 6.723932 13.1566 27.83 9701 0.1300 6.551458 13.5045 14.20 4949 0.0900 6.359432 13.9143 30.57 10656 0.1100 6.130010 14.4378 21.33 7435 0.1300 5.853018 15.1249 36.40 12687 0.1100 5.626204 15.7385 15.49 5401 0.1300 5.507643 16.0795 23.25 8106 0.1000 5.447238 16.2590 13.21 4606 0.0870 5.224449 16.9573 19.21 6697 0.1100 5.160516 17.1690 17.10 5961 0.0870 5.083475 17.4312 14.74 5137 0.1100 4.954247 17.8896 19.64 6848 0.1000 4.863750 18.2252 28.34 9879 0.0800 4.805168 18.4494 46.26 16125 0.0700 4.756883 18.6383 49.99 17425 0.0800 4.656926 19.0420 19.10 6659 0.1900 4.630194 19.1530 17.96 6260 0.0870 4.566015 19.4248 21.34 7438 0.1000 4.487514 19.7680 12.76 4447 0.1000 4.347753 20.4101 11.69 4074 0.1100 4.301465 20.6322 19.17 6682 0.0900 4.224555 21.0120 14.55 5072 0.0870 4.186561 21.2049 23.33 8134 0.1700 4.065767 21.8425 26.06 9084 0.1000 4.015560 22.1190 17.10 5929 0.1000 3.976949 22.3365 14.98 5223 0.0500 3.935785 22.5732 34.50 12028 0.1100 3.867038 22.9799 100.00 34859 0.1000 3.779481 23.5198 40.14 13991 0.0800 3.742319 23.7567 59.68 20805 0.1000 3.710418 23.9640 13.17 4591 0.0870 3.645564 24.3968 11.19 3902 0.0800 3.621808 24.5593 18.71 6524 0.1000 3.552536 25.0459 16.01 5581 0.1000 3.516088 25.3098 13.46 4691 0.0600 3.498357 25.4402 12.66 4413 0.0700 3.467075 25.6737 10.74 3745 0.0500 3.418947 26.0414 21.49 7491 0.1000 3.395298 26.2260 12.12 4225 0.0870 3.369948 26.4268 15.48 5369 0.0700 3.358554 26.5181 14.33 4995 0.0600 3.244985 27.4641 11.90 4149 0.0700 3.229427 27.5990 9.63 3356 0.0870 3.177657 28.0578 15.07 5253 0.1200 3.144884 28.3562 32.65 11381 0.1000 3.106130 28.7176 9.83 3425 0.0800 3.082970 28.9380 9.00 3138 0.0870 3.056106 29.1980 8.56 2984 0.0870 3.032184 29.4335 8.74 3048 0.1100 2.994539 29.8121 8.27 2884 0.0700 2.979114 29.9700 9.26 3229 0.0800 2.924922 30.5387 9.19 3203 0.1800 2.870290 31.1346 16.32 5689 0.1400 2.828902 31.6019 13.59 4737 0.1100 2.762611 32.3808 10.83 3775 0.1000

Example 6 [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl-,; Raloxifene L-lactate (¼ H₂O)

37.9 g (˜0.6 mol) pulverized potassium hydroxide (>85%) is dissolved in 1250 ml 2-propanol, with stirring and addition of nitrogen, over approximately 30 minutes. 100 g (0.196 mol) raloxifene hydrochloride is added in small portions in such a way that temperature is kept below 30° C. After addition of raloxifene hydrochloride, the deep red suspension is stirred for 30-45 minutes until a deep red solution appears. Reminiscence of insoluble product may be filtered off

A solution of 67.6 g 85% L-lactic acid (0.6 mol) is added with violent stirring during 1-1.5 hours. The mixture is now stirred further at room temperature for 18 hours. If no or very little precipitate appears in the solution the reaction mixture is filtered and 2-propanol is evaporated off. To the reminisce is now added 150 ml of water with stirring and the precipitated product is collected by filtration and dried in vacuo at 55-65° C. Next the crude product is recrystallized from 160 ml 96% ethanol (if necessary seeding crystals are added) to give 62.8 g (56.4%) of the product.

Mp: 171-173° C.:

Elemental analysis C₃₁H₃₃NO₇S (¼H₂O):

Calculated: C, 65.52%; H, 5.94%; N, 2.47%; S, 5.64%

Found: C, 65.50%; H, 5.85%; N, 2.50%; S, 5.74%

IR:

3159 cm⁻¹, 2935 cm⁻¹, 2806 cm⁻¹, 2672 cm⁻¹, 1643 cm⁻¹, 1598 cm⁻¹, 1574 cm⁻¹, 1547 cm⁻¹, 1501 cm⁻¹, 1466 cm⁻¹, 1422 cm⁻¹, 1347 cm⁻¹, 1308 cm⁻¹, 1269 cm⁻¹, 1229 cm⁻¹, 1171 cm⁻¹, 1119 cm⁻¹, 1067 cm⁻¹, 1037 cm⁻¹, 1006 cm⁻¹, 908 cm⁻¹, 835 cm⁻¹, 807 cm⁻¹, 665 cm⁻¹, 649 cm⁻¹, 634 cm⁻¹, 623 cm⁻¹, 513 cm⁻¹.

The product was analysed using differential scanning calorimetry using a METTLER TOLEDO STAR® system, according to the instructions of the manufacturer. The differential scanning calorimetric chart (DSC) is shown in FIG. 5.

Further the product was analysed by X-ray diffraction analysis using the STOE Powder diffraction system. The result is shown in FIG. 6, and is also listed numerically below.

XRD: D 2Theta I(rel) I(abs) FWHM 14.079244 6.2726 45.93 16568 0.1300 9.974912 8.8580 32.43 11699 0.1100 9.526523 9.2758 71.31 25721 0.1200 8.215598 10.7600 47.82 17248 0.1100 7.246270 12.2045 80.04 28871 0.1100 7.065557 12.5178 16.17 5832 0.0700 6.878001 12.8606 22.74 8201 0.1200 6.283709 14.0828 66.27 23901 0.0800 6.194698 14.2862 53.98 19470 0.0984 5.859529 15.1080 11.17 4028 0.0984 5.744935 15.4112 16.16 5828 0.1200 5.312222 16.6751 18.02 6499 0.1200 5.046910 17.5585 34.26 12356 0.0900 4.978933 17.8001 54.66 19715 0.1000 4.918535 18.0205 17.40 6277 0.0984 4.746264 18.6804 26.77 9655 0.1000 4.712771 18.8143 46.35 16716 0.0900 4.569429 19.4101 57.60 20777 0.1000 4.455985 19.9093 53.60 19332 0.1200 4.345589 20.4204 12.70 4579 0.0900 4.268096 20.7952 86.33 31139 0.0900 4.106332 21.6241 20.17 7274 0.1100 4.042283 21.9710 22.73 8197 0.1200 3.944656 22.5218 23.46 8462 0.1000 3.913129 22.7056 100.00 36069 0.1100 3.831706 23.1947 15.49 5586 0.0900 3.777075 23.5350 69.72 25148 0.1400 3.735872 23.7983 14.85 5358 0.0984 3.667856 24.2463 11.94 4305 0.0900 3.639035 24.4413 13.87 5001 0.0800 3.589918 24.7809 9.38 3383 0.0984 3.545715 25.0949 23.58 8505 0.0800 3.505655 25.3864 33.63 12131 0.1100 3.442223 25.8622 22.60 8152 0.1100 3.411017 26.1030 10.82 3901 0.0984 3.371851 26.4117 44.16 5108 0.1000 3.280618 27.1600 15.23 5494 0.1100 3.251104 27.4114 14.23 5134 0.0800 3.232072 27.5760 19.25 6943 0.1100 3.153056 28.2812 12.42 4479 0.1900 3.143130 28.3724 12.29 4432 0.0984 3.081939 28.9479 17.16 6189 0.2200 3.040378 29.3524 9.73 3510 0.1300 2.990508 29.8532 15.29 5514 0.1400 2.929711 30.4876 11.37 4102 0.1200 2.892397 30.8906 18.91 6822 0.1200 2.856192 31.2922 8.91 3214 0.1100 2.818108 31.7261 14.79 5336 0.2500 2.765584 32.3450 15.86 5720 0.1300

Example 7 Preparation of [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl-, L-lactate; Raloxifene L-lactate

40 g (0.06 mol) 6-methylsulphonyloxy-2-(4-methylsulphonyloxyphenyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl-, hydrochlorid, having the structural formula below

is suspended in 385 ml 2-propanol. 21.75 g (0.33 mol) powdered 85% potassium hydroxide is added with stirring, and the mixture is heated to reflux for 2 hour. The deep red solution is cooled to room temperature, and a solution of 20.3 g 85% L-lactic acid (0.18 mol) is added with violent stirring during 1-1.5 hours, and thereafter the 2-propanol is evaporated off to give the crude product. The product is recrystallized from approximately 50 ml 96% ethanol to give the title compound.

Example 8 (Comparative Example) Dissolution of Raloxifene Hydrochloride in Dilute Hydrochloric Acid or Phosphoric Acid

60 mg raloxifene HCl was transferred to a dissolution vessel containing one litre 0.1 M HCl. The mixture was vigorously mixed and left at room temperature over night. Subsequently the dissolution was evaluated visually. Very little of the initial added amount of raloxifene hydrochloride was dissolved shown by the presence of solid material at the bottom of the vessel and essentially no colouring of the fluid.

A similar dissolution test was performed using 60 mg raloxifene hydrochloride in 0.1 M phosphoric acid. In this case all raloxifene hydrochloride seemed to be dissolved indicated by the absence of solids on the bottom of the vessel and a strong yellow colouring of the fluid in the vessel.

Example 9 Dissolution of Raloxifene Acid Addition Salts or Solvates in Dilute Hydrochloric Acid or Phosphoric Acid

Using same procedures as in example 8, raloxifene succinate, raloxifene DL-lactate hemihydrate, raloxifene L-lactate hemihydrate, raloxifene malonate and raloxifene sulphate (2-propanol solvate) were tested for dissolution in dilute hydrochloric acid or phosphorous acid.

All these tests showed complete dissolution shown be absence of solids in the vessel and strong colouring of the liquid.

Example 10 Intrinsic Dissolution Rate of Raloxifene Acid Addition Salts in Dilute Phosphoric Acid Compared with Dilute Hydrochloric Acid

Experimental set-up:

The intrinsic dissolution rate of raloxifene succinate, raloxifene DL-lactate hemihydrate, raloxifene L-lactate ¼-hydrate, raloxifene L-lactate hemihydrate, raloxifene malonate, raloxifene sulphate (2-propanol solvate) and raloxifene hydrochloride were tested in dilute solutions of hydrochloric acid and in dilute solutions of phosphorous acid containing NaCl in amounts so the chloride ion concentration in each solution was 0.1 M. The tests were performed at 37° C. and at pH of 1, 2, 3, 4, and 5, respectively. The raloxifene hydrochloride salt used in these experiments was purchased from Otto Bradt GmbH (batch MA/RF/12003) while the rest of the raloxifene acid additions salts were prepared according to Example 1-6.

The experiments were carried out following the procedure of Rotation Disc Method (USP 1087) using Vankel VK 7000 Intrinsic dissolution apparatus (Vankel Technology group, W. Vankelion) equipped with Vankel 12-4120 intrinsic disc having a surface area of 0.5 cm², Vankel 12-4130 surface plate, Vankel 12-4140 punch, and Vankel shaft and holder (surface area: 0.5 cm²) and operating at a rotation rate of 100 rpm.

The buffer solution is handled in a 750 ml measuring bottle, degassed and transferred into a dissolution vessel. Approximately 100 mg compound is weighed out and transferred into an intrinsic disc. Said disc is then assembled, and to said disc a disc is applied in the IR-press at a pressure of 5 kN for 1 minute. The disc is started and samples of 10 ml are collected by use of “pressure vials” after 1, 10, 20, 30, 45, and 60 minutes. The change of volume is corrected using the equation: Q=Vs×(sumCn−1)+Cn×Vt wherein Q designates the volume at the time t, C designates the concentration of the sample n, Vt designates the volume of the liquid collected at the time t, and Vs designates the volume of the sample collected. The sample is measured against a standard using HPLC. In these measurements a 5 microns 3.9×150 mm column filled with symmetrical material is employed and as eluant a 20 mM phosphate buffer KH₂PO₄, pH 6.8 mixed with acetonitrile and tetrahydrofuran in the ratio 55:35:10 is used.

Preparation of Standard Solution:

The standard is prepared by use of following procedure: 20 mg of salt is dissolved initially in 100 ml of MeOH and then 1 ml of this solution is transferred to a 50 ml flask with water and then 2 ml to a 20 ml flask of buffer in question.

Preparation of Buffer Solutions:

pH 1: a 0.1 M HCl is used.

0.025 M Phosphate buffer solution pH 2.0: 3.40 g of potassium dihydrogen phosphate is dissolved in 900 ml of water. Then pH is adjusted to 2.0 with phosphoric acid and diluted to 1000.0 ml with water. Exactly 5.85 g of NaCl is added to 1 L of buffer.

0.025 M Phosphate buffer solution pH 3.0: 3.40 g of potassium dihydrogen phosphate is dissolved in 900 ml of water. Then pH is adjusted to 3.0 with phosphoric acid and diluted to 1000.0 ml with water. Exactly 5.85 g of NaCl is added to 1 L of buffer.

0.022 M Phosphate buffer solution pH 4.0: 3.0 g of potassium dihydrogen phosphate is dissolved in 800 ml of water. Then pH is adjusted with 1 M potassium hydroxide and phosphoric acid and diluted to 1000.0 ml with water. Exactly 5.85 g of NaCl is added to 1 L of buffer.

0.02 M Phosphate buffer solution pH 5.0: 2.72 g of potassium dihydrogen phosphate is dissolved in 800 ml of water. Then pH is adjusted with 1 M potassium hydroxide and diluted to 1000.0 ml with water. Exactly 5.85 g of NaCl is added to 1 L of buffer.

Results

The results from above described experiment comparing the ID of the various raloxifene acid addition salts in dilute solutions of phosphorous acid and hydrochloric acid, respectively, is given in the table below. The numbers in the table represent the average of two measurements. DL-lactate L-lactate hemi- L-Lactate hemi- Buffer solution Succinate hydrate ¼-hydrate hydrate Malonate Sulphate Hydrochloride Hydrochloride, 0.0550 0.0056 0.0035 0.0475 0.0229 0.0036 0.0022 pH 1 Phosphate, 0.0228 0.0119 0.0028 0.0453 0.0173 0.0137 0.0026 pH 2 Phosphate, 0.0271 0.0062 0.0067 0.0403 0.0148 0.0052 0.0022 pH 3 Phosphate, 0.0127 0.0212 0.0324 0.0190 0.0136 0.0109 0.0022 pH 4 Phosphate, 0.0119 0.0215 0.0247 0.0091 0.0112 0.0081 0.0044 pH 5 The intrinsic dissolution rate (IDR) in (μmol/min * cm²) of various acid addition salts of raloxifene determined by the method described above. The numbers represent the average of two measurements.

Graphic displays of the results are shown in the FIGS. 7-12. The results show very clearly that the intrinsic dissolution rate is markedly higher for the raloxifene acid addition salts and/or solvates thereof according to the invention compared with raloxifene hydrochloride. 

1. Raloxifene acid addition salt or solvate thereof wherein the raloxifene acid addition salt of solvate thereof is selected among: raloxifene D-lactate, raloxifene L-lactate, Raloxifene DL-lactate, raloxifene D-lactate hemihydrate, raloxifene D-lactate ¼-hydrate, raloxifene L-lactate hemihydrate, raloxifene L-lactate ¼-hydrate, raloxifene DL-lactate hemihydrate and raloxifene DL-lactate ¼-hydrate.
 2. Raloxifene acid addition salt or solvate thereof according to claim 1, wherein the raloxifene acid addition salt or solvate thereof is raloxifene L-lactate hemihydrate being in crystalline form having the following X-ray crystalline positions: XRD: D 2Theta I(rel) I(abs) FWHM 14.639874 6.0322 17.56 6122 0.1200 13.207421 6.6871 15.07 5254 0.1200 10.875932 8.1229 80.41 28029 0.1200 9.268456 9.5347 22.67 7903 0.1200 8.140638 10.8593 17.92 6247 0.1200 7.488503 11.8083 15.59 5433 0.1000 7.310331 12.0971 12.47 4347 0.0800 7.089508 12.4754 25.79 8991 0.1000 6.931874 12.7603 12.78 4454 0.0900 6.723932 13.1566 27.83 9701 0.1300 6.551458 13.5045 14.20 4949 0.0900 6.359432 13.9143 30.57 10656 0.1100 6.130010 14.4378 21.33 7435 0.1300 5.853018 15.1249 36.40 12687 0.1100 5.626204 15.7385 15.49 5401 0.1300 5.507643 16.0795 23.25 8106 0.1000 5.447238 16.2590 13.21 4606 0.0870 5.224449 16.9573 19.21 6697 0.1100 5.160516 17.1690 17.10 5961 0.0870 5.083475 17.4312 14.74 5137 0.1100 4.954247 17.8896 19.64 6848 0.1000 4.863750 18.2252 28.34 9879 0.0800 4.805168 18.4494 46.26 16125 0.0700 4.756883 18.6383 49.99 17425 0.0800 4.656926 19.0420 19.10 6659 0.1900 4.630194 19.1530 17.96 6260 0.0870 4.566015 19.4248 21.34 7438 0.1000 4.487514 19.7680 12.76 4447 0.1000 4.347753 20.4101 11.69 4074 0.1100 4.301465 20.6322 19.17 6682 0.0900 4.224555 21.0120 14.55 5072 0.0870 4.186561 21.2049 23.33 8134 0.1700 4.065767 21.8425 26.06 9084 0.1000 4.015560 22.1190 17.10 5929 0.1000 3.976949 22.3365 14.98 5223 0.0500 3.935785 22.5732 34.50 12028 0.1100 3.867038 22.9799 100.00 34859 0.1000 3.779481 23.5198 40.14 13991 0.0800 3.742319 23.7567 59.68 20805 0.1000 3.710418 23.9640 13.17 4591 0.0870 3.645564 24.3968 11.19 3902 0.0800 3.621808 24.5593 18.71 6524 0.1000 3.552536 25.0459 16.01 5581 0.1000 3.516088 25.3098 13.46 4691 0.0600 3.498357 25.4402 12.66 4413 0.0700 3.467075 25.6737 10.74 3745 0.0500 3.418947 26.0414 21.49 7491 0.1000 3.395298 26.2260 12.12 4225 0.0870 3.369948 26.4268 15.48 5369 0.0700 3.358554 26.5181 14.33 4995 0.0600 3.244985 27.4641 11.90 4149 0.0700 3.229427 27.5990 9.63 3356 0.0870 3.177657 28.0578 15.07 5253 0.1200 3.144884 28.3562 32.65 11381 0.1000 3.106130 28.7176 9.83 3425 0.0800 3.082970 28.9380 9.00 3138 0.0870 3.056106 29.1980 8.56 2984 0.0870 3.032184 29.4335 8.74 3048 0.1100 2.994539 29.8121 8.27 2884 0.0700 2.979114 29.9700 9.26 3229 0.0800 2.924922 30.5387 9.19 3203 0.1800 2.870290 31.1346 16.32 5689 0.1400 2.828902 31.6019 13.59 4737 0.1100 2.762611 32.3808 10.83 3775 0.1000


3. Raloxifene acid addition salt or solvate thereof according to claim 1, wherein the raloxifene acid addition salt or solvate thereof is raloxifene L-lactate ¼-hydrate being in crystalline form having the following X-ray crystalline positions: XRD: D 2Theta I(rel) I(abs) FWHM 14.079244 6.2726 45.93 16568 0.1300 9.974912 8.8580 32.43 11699 0.1100 9.526523 9.2758 71.31 25721 0.1200 8.215598 10.7600 47.82 17248 0.1100 7.246270 12.2045 80.04 28871 0.1100 7.065557 12.5178 16.17 5832 0.0700 6.878001 12.8606 22.74 8201 0.1200 6.283709 14.0828 66.27 23901 0.0800 6.194698 14.2862 53.98 19470 0.0984 5.859529 15.1080 11.17 4028 0.0984 5.744935 15.4112 16.16 5828 0.1200 5.312222 16.6751 18.02 6499 0.1200 5.046910 17.5585 34.26 12356 0.0900 4.978933 17.8001 54.66 19715 0.1000 4.918535 18.0205 17.40 6277 0.0984 4.746264 18.6804 26.77 9655 0.1000 4.712771 18.8143 46.35 16716 0.0900 4.569429 19.4101 57.60 20777 0.1000 4.455985 19.9093 53.60 19332 0.1200 4.345589 20.4204 12.70 4579 0.0900 4.268096 20.7952 86.33 31139 0.0900 4.106332 21.6241 20.17 7274 0.1100 4.042283 21.9710 22.73 8197 0.1200 3.944656 22.5218 23.46 8462 0.1000 3.913129 22.7056 100.00 36069 0.1100 3.831706 23.1947 15.49 5586 0.0900 3.777075 23.5350 69.72 25148 0.1400 3.735872 23.7983 14.85 5358 0.0984 3.667856 24.2463 11.94 4305 0.0900 3.639035 24.4413 13.87 5001 0.0800 3.589918 24.7809 9.38 3383 0.0984 3.545715 25.0949 23.58 8505 0.0800 3.505655 25.3864 33.63 12131 0.1100 3.442223 25.8622 22.60 8152 0.1100 3.411017 26.1030 10.82 3901 0.0984 3.371851 26.4117 44.16 5108 0.1000 3.280618 27.1600 15.23 5494 0.1100 3.251104 27.4114 14.23 5134 0.0800 3.232072 27.5760 19.25 6943 0.1100 3.153056 28.2812 12.42 4479 0.1900 3.143130 28.3724 12.29 4432 0.0984 3.081939 28.9479 17.16 6189 0.2200 3.040378 29.3524 9.73 3510 0.1300 2.990508 29.8532 15.29 5514 0.1400 2.929711 30.4876 11.37 4102 0.1200 2.892397 30.8906 18.91 6822 0.1200 2.856192 31.2922 8.91 3214 0.1100 2.818108 31.7261 14.79 5336 0.2500 2.765584 32.3450 15.86 5720 0.1300


4. Raloxifene acid addition salt or solvate thereof according to claim 1, wherein the raloxifene acid addition salt or solvate thereof is raloxifene DL-lactate hemihydrate being in crystalline form having the following X-ray crystalline positions: XRD: D 2Theta I(rel) I(abs) FWHM 13.595814 6.4959 28.40 12683 0.1400 10.855533 8.1382 16.15 7211 0.1200 9.849394 8.9711 32.17 14369 0.1000 9.534325 9.2682 66.95 29898 0.1300 8.150249 10.8465 45.20 20188 0.1300 7.240730 12.2138 63.53 28374 0.1400 6.769843 13.0670 18.42 8227 0.1500 6.272666 14.1077 75.67 33794 0.1900 5.818832 15.2143 13.28 5933 0.2000 5.657337 15.6513 18.07 8070 0.1300 5.505030 16.0872 10.51 4692 0.1000 5.261933 16.8357 17.48 7806 0.1400 5.089504 17.4104 16.14 7210 0.1000 5.001569 17.7189 41.94 18732 0.0900 4.958950 17.8725 29.16 13023 0.1148 4.797388 18.4795 19.39 8660 0.1100 4.669322 18.9910 49.20 21972 0.1400 4.574684 19.3876 63.21 28227 0.1000 4.533019 19.5676 44.94 20071 0.1148 4.440548 19.9792 32.70 14604 0.1200 4.301886 20.6301 100.00 44659 0.1500 4.155406 21.3657 78.00 34833 0.1600 4.059049 21.8797 27.53 12296 0.1800 3.960846 22.4285 25.59 11427 0.1000 3.907408 22.7393 83.48 37282 0.1200 3.865461 22.9894 16.46 7350 0.1148 3.828892 23.2120 17.46 7798 0.0900 3.773130 23.5599 50.71 22649 0.1200 3.716486 23.9243 23.06 10300 0.1300 3.652238 24.3515 15.79 7053 0.1800 3.584725 24.8174 12.91 5764 0.1500 3.486791 25.5261 30.45 13600 0.1200 3.439149 25.8858 22.21 9919 0.1300 3.396267 26.2184 17.86 7978 0.1100 3.370045 26.4261 12.48 5572 0.1148 3.329320 26.7553 9.21 4113 0.1100 3.292728 27.0582 11.81 5274 0.1000 3.278070 27.1815 11.25 5026 0.1148 3.218620 27.6935 21.24 9485 0.1900 3.167986 28.1452 13.80 6162 0.0900 3.143230 28.3715 30.33 13546 0.1000 3.095423 28.9191 14.02 6260 0.1200 3.024921 29.5058 11.56 5161 0.1400 3.007253 29.6831 13.40 5984 0.1300


5. Raloxifene acid addition salt or solvate thereof being raloxifene succinate in crystalline form having the following X-ray crystallographic positions: XRD: D 2Theta I(rel) I(abs)) FWHM 13.195230 6.6933 20.78 8475 0.1400 9.695642 9.1137 13.43 5476 0.0300 9.304945 9.4972 18.19 7419 0.1300 8.394523 10.5300 13.26 5407 0.1000 7.944460 11.1283 14.15 5768 0.1000 7.708667 11.4699 17.61 7180 0.1200 7.526675 11.7482 12.32 5023 0.0898 7.323294 12.0756 15.22 6205 0.1000 7.160495 12.3512 13.04 5316 0.0800 6.926815 12.7696 23.68 9655 0.1300 6.606409 13.3917 29.08 11856 0.1400 6.463392 13.3894 14.45 5891 0.0898 6.285432 14.0789 21.24 8662 0.1200 6.127742 14.4432 63.63 25947 0.1200 5.961999 14.8469 15.55 6342 0.0900 5.875574 15.0665 15.77 6430 0.0898 5.788967 15.2933 16.15 6585 0.1400 5.624221 15.7441 34.74 14167 0.1200 5.453763 16.2394 22.89 9334 0.1300 5.276560 16.7887 12.71 5182 0.1200 5.095057 17.3913 14.19 5786 0.1100 5.020392 17.6520 11.12 4535 0.0898 4.835944 18.3309 18.30 7461 0.1200 4.765096 18.6059 18.62 7591 0.1100 4.630456 19.1519 65.88 26864 0.1600 4.525518 19.6003 15.16 6180 0.0800 4.484997 19.7792 24.48 9982 0.1000 4.376528 20.2745 18.78 7659 0.1000 4.352225 20.3889 19.11 7790 0.1000 4.227757 20.9959 29.39 11984 0.1000 4.191265 21.1808 56.82 23171 0.0800 4.158052 21.3520 40.16 16377 0.0898 4.101947 21.6475 17.14 6988 0.0800 4.062068 21.8626 19.79 8072 0.1000 4.010082 22.1496 11.70 4771 0.0600 3.921660 22.6556 100.00 40776 0.1300 3.860487 23.0194 29.04 11842 0.1100 3.813566 23.3066 19.25 7850 0.1100 3.732687 23.8189 19.33 7884 0.1300 3.694791 24.0669 22.47 9161 0.1100 3.644300 24.4054 18.84 7680 0.1400 3.544078 25.1067 13.63 5556 0.0700 3.496160 25.4565 16.28 6637 0.0898 3.446458 25.8299 20.36 8300 0.2100 3.398344 26.2021 12.35 5036 0.1200 3.373032 26.4022 8.82 3597 0.0898 3.305938 26.9481 14.08 5741 0.1100 3.281940 27.1489 10.08 4112 0.0898 3.260437 27.3314 9.66 3937 0.0898 3.227083 27.6194 19.22 7838 0.1200 3.179256 28.0434 16.28 6640 0.2600 3.146269 28.3435 8.89 3627 0.0898 3.121159 28.5764 9.58 3907 0.0900 3.097691 28.7975 10.64 4337 0.0400 3.074307 29.0213 19.64 8008 0.1200 3.032262 29.4328 10.17 4148 0.1300 3.010128 29.6541 9.43 3847 0.0898


6. Raloxifene acid addition salt or solvate thereof being raloxifene sulphate 2-propanol solvate.
 7. Raloxifene acid addition salt or solvate thereof according to claim 6, wherein raloxifene sulphate 2-propanol solvate is in crystalline form having the following X-ray crystallographic positions: XRD: D 2Theta I(rel) I(abs) FWHM 14.374007 6.1439 26.57 5009 0.0900 10.303750 8.5748 29.62 5583 0.1300 9.201529 9.6042 26.22 4942 0.1100 8.871726 9.9621 29.84 5624 0.1300 8.569965 10.3138 22.25 4195 0.0400 8.320378 10.6241 25.97 4896 0.1200 7.945119 11.1274 38.65 7286 0.1300 7.514174 11.7678 20.56 3876 0.1041 7.205108 12.2745 25.04 4721 0.1400 6.537437 13.5336 66.78 12590 0.1400 6.228787 14.2076 21.88 4126 0.1100 5.628329 15.7325 20.71 3904 0.0900 5.540447 15.9837 27.40 5166 0.1100 5.322476 16.5489 64.98 12249 0.1500 5.138694 17.2425 21.65 4082 0.1100 5.020317 17.6522 64.05 12074 0.1400 4.706881 18.8381 100.00 18851 0.1300 4.618097 19.2036 60.47 11400 0.0800 4.538129 19.5453 59.35 11189 0.1100 4.471816 19.8381 67.03 12636 0.1200 4.261964 20.8255 54.78 10327 0.1100 4.204757 21.1121 51.35 9680 0.1600 4.156029 21.3625 46.65 8794 0.1041 4.093305 21.6938 25.93 4888 0.0900 4.035960 22.0058 24.21 4563 0.1800 3.937182 22.5651 25.37 4784 0.1200 3.835400 23.1721 22.17 4179 0.0900 3.796528 23.4127 40.94 7718 0.0900 3.767170 23.5978 61.03 11505 0.1100 3.691303 24.0899 20.10 3790 0.1500 3.639317 24.4393 47.20 8897 0.1200 3.590489 24.7769 28.23 5321 0.1600 3.511060 25.3467 29.66 5592 0.1100 3.478586 25.5873 23.70 4468 0.1041 3.416539 26.0601 37.38 7047 0.1900 3.355389 26.5436 20.28 3823 0.1300 3.314637 26.8760 17.08 3220 0.1200 3.271015 27.2413 15.24 2874 0.0600 3.252583 27.3987 14.71 2773 0.1041 3.100446 28.7714 23.04 4344 0.1200 3.079703 28.9694 19.73 3720 0.1041 3.033828 29.4172 29.23 5511 0.1300 3.009744 29.6580 15.28 2880 0.1041 2.937725 30.4024 13.30 2507 0.1700


8. Raloxifene acid addition salt or solvate thereof being raloxifene malonate in crystalline form having the following X-ray crystalline positions: XRD: D 2Theta I(rel) I(abs) FWHM 14.385166 6.1391 36.51 6471 0.0100 13.125024 6.7292 38.91 6896 0.1300 10.305386 8.5734 37.32 6614 0.1700 9.279238 9.5236 39.85 7062 0.1300 8.860721 9.9745 34.60 6133 0.0900 8.510328 10.3863 33.27 5895 0.0900 8.314361 10.6318 33.02 5852 0.0800 7.947949 11.1234 41.61 7375 0.1600 7.265135 12.1727 35.79 6343 0.1300 6.882996 12.8512 29.65 5254 0.0300 6.537915 13.5326 60.19 10667 0.1800 6.258251 14.1404 61.12 10833 0.2100 6.003203 14.7444 31.92 5657 0.1200 5.877911 15.0605 29.17 5170 0.0600 5.794580 15.2784 29.33 5198 0.0200 5.663226 15.6349 49.63 8796 0.1300 5.550457 15.9547 36.61 6487 0.0800 5.354103 16.5438 55.84 9897 0.2200 5.134028 17.2583 30.18 5349 0.1378 5.023848 17.6397 55.21 9784 0.2100 4.836637 18.3283 36.13 6404 0.1400 4.700761 18.8628 71.64 12696 0.1600 4.644808 19.0922 86.46 15323 0.1500 4.538522 19.5436 61.36 10874 0.1300 4.472256 19.8361 50.40 8931 0.1000 4.347111 20.4132 37.86 6709 0.1000 4.247918 20.8951 88.12 15616 0.2300 4.161428 21.3344 73.93 13101 0.1600 4.085803 21.7341 37.19 6591 0.1100 4.019584 22.0966 35.60 6309 0.1500 3.921695 22.6554 100.00 17722 0.1700 3.765729 23.6059 50.70 8986 0.2000 3.703455 24.0097 34.79 6166 0.1200 3.638542 24.4446 47.30 8382 0.1900 3.499221 25.4339 44.29 7849 0.2000 3.426872 25.9801 43.63 7732 0.2200 3.292398 27.0610 23.39 4145 0.1000 3.253755 27.3886 25.03 4435 0.1400 3.192249 27.9269 22.18 3931 0.1400 3.094846 28.8246 28.68 5083 0.3000 3.034329 29.4123 27.30 4338 0.1900.

9-10. (canceled)
 11. Pharmaceutical composition capable of fast and reliable release of the active ingredients in gastric juice, comprising a raloxifene acid addition salt or solvate thereof according to claim
 1. 12. Pharmaceutical composition according to claim 11, wherein the pharmaceutical is intended for the treatment of cancer or osteoporosis, or for inhibiting cartilage degradation.
 13. Process for the manufacture of raloxifene lactate comprising the following steps: to a solution of the compound having the general formula I in an solvent

wherein R represents two independently selected hydroxyl protection groups, a suitable reagent is added in order to remove the protection groups; lactic acid is added to the mixture, and raloxifene lactate is precipitated from the mixture and isolated.
 14. Process according to claim 13, wherein the groups R are independently selected from: C₁-C₄ alkyl, C₅-C₇ cycloalkyl, benzyl —COR² or SO₂R², wherein R² is C₁-C₄ primary or secondary alkyl, C₁-C₃ fluoroalkyl, C₁-C₃ chloroalkyl, C₁-C₄ alkylphenyl, C₁-C₄ alkoxyphenyl, mono- or dinitrophenyl or mono- or di(chloro or fluoro)phenyl.
 15. Process according to claim 13, wherein the two R groups are identical.
 16. Process according to the claim 13, wherein the solvent is selected from alcohols having 1 to 5 carbon atoms.
 17. Process according to claim 16, wherein the alcohol is a monovalent alcohol.
 18. Process according to claim 17, wherein the alcohol is ethanol.
 19. Process according to claim 18, wherein the alcohol is 96% ethanol.
 20. Process according to claim 13, wherein the lactate is L-lactate. 